The structural formula of halogenated vinyl arabinosyl uracil is shown below: ##STR1## where X is halogen.
The compounds are properly named 1-(.beta.-D-arabinofuranosyl)-5(E)-(2-halogenovinyl) uracil, but are commonly referred to as "XVaraU", where X is halogen. When the compounds are radiohalogenated, the common designation is [.sup.* X]XVaraU, where .sup.* X represents the particular radiohalogen.
In regard to the halogen, while any of the halogens can be substituted on the vinyl group, the preferred radiohalogens are iodine and bromine. Certain radioisotopes of the halogens have half lives and modes of decay which limit patient dosage. Further, the gamma ray energy of some isotopes is better suited to detection devices. Therefore, some halogens and isotopes are either more useful or more practical or more available or less expensive than others. Thus, the invention will be described mainly in connection with the better suited and preferred halogens, i.e. iodine and bromine, and in regard to preferred isotopes thereof.
The invention is useful in diagnosis of and treatment of viral diseases, especially viral diseases which adversely affect the brain, and more specially, such diseases where the presence of the virus is difficult to detect by external examination of the human body. A notable example of the foregoing is viral encephalitis in man. Diagnosis of viral encephalitis is difficult because accurate methods for the non-invasive detection of the virus in the host brain cells have not been developed, and, as can be easily appreciated, the clinician is most reluctant to harvest brain tissue from a patient unless encephalitis is most strongly suspected.
An example of the foregoing, and one of the infections specifically exemplified herein, is HSV type 1 herpes virus, which is a major cause of severe sporadic encephalitis in man. Early symptoms of HSV encephalitis, include personality change, behavioral disturbance, seizures and mutism, and are anatomically explained by the predilection for the infectious process to involve the medial temporal lobe, orbital frontal lobe and other "limbic" areas of the brain. Late in the disease, destruction of these and other areas of the brain readily indicates the presence of the disease, but early in the disease, when diagnosis and institution of therapy are most important, such symptoms may be due to other causes, such as reversible physiological disturbance. It is to this early phase of such infections that the present invention is directed, since it is during this early phase, especially the first 72 hours after the onset of symptoms, that effective antiviral chemotherapy may be instituted.
A major impediment to effective early management of such infections, e.g. HSV encephalitis, is the lack of a reliable, non-invasive test which will allow early diagnosis. Unfortunately, present neurodiagnostic studies such as CT and radionuclide scanning may yield normal results early in such diseases and viral serology is only retrospectively useful, and even then may not be definitive. At present, a brain biopsy is the only definitive means of early diagnosis, but the biopsy is a major medical procedure. Therefore, the clinician is left with a difficult decision which may result in delayed or inappropriate therapy. Clearly, there is a need for an improved non-invasive diagnostic method for diseases of this nature.
An early attempt at providing such diagnostic methods is disclosed in U.S. Pat. No. 4,211,773 to Price. Price proposed a non-invasive diagnosis for HSV-1 encephalitis as follows. Selective uptake by infected cells of a radioactive (gamma ray emitting) antiviral drug serves as a substrate for virus-coded thymidine kinase. The "trapped" phosphorylated radioactive antiviral compounds can then be visualized using gamma ray scintigraphy or PET imaging. Price made the specific proposal that radiolabelled 5-substituted 1-(-2'deoxy-2'substituted)arabinofuranosyl pyrimidine nucleosides could be useful as tracers for such a scintigraphic diagnosis. Prompted by the disclosure of Price, others prepared and assayed potential radionucleoside tracer compounds of the anti-herpes class. Unfortunately, it was found that none of the radiotracer compounds was suitable, for a variety of complex reasons.
The present invention is concerned with derivatives of XVaraU and especially I- and BrVaraU. Recently, IVaraU was shown (along with BrVaraU) as an unlabelled antiherpes drug.
U.S. Pat. No. 4,386,076 discloses XVaraU and shows experimental results in halogenating the vinyl arabinosyl uracil with bromine and chlorine to produce the corresponding BrVaraU or C1VaraU. The patent, however, provides no experimental details in regard to IVaraU.
However, recently S. Sacks (see Abstract 97 of the 1988 proceedings of the Interscience Conference on Antimicrobial Agents and Chemotherapy) disclosed that [.sup.123 I]IVaraU is concentrated in herpes infected tissue. This compound is an arabinosyl uridine derivative, not a 2'substituted 2'deoxy arabinosyt uridine, as specified in the Price patent. Thus, the compound [.sup.123 X]XVaraU promised to become important as a practical radiotracer for herpes.
While [.sup.123 I]IVaraU is, therefore, a valuable compound for the above purposes, it was discovered that this compound and related [.sup.* X]XVaraU compounds also have serious disadvantages when prepared in administrable composition form. In this regard, certain criteria must be satisfied in order to provide a satisfactory administrable form. Considering the high cost of .sup.123 I and the rather short half life of 13.3 hours, it is firstly necessary that radiolabelling utilizing .sup.123 I be nearly quantitative and secondly that the process of labelling must be of short time duration. Thirdly, the labelling process must be straightforward and with few complications, so as to be conductible by technicians, e.g. hospital technicians (nuclear medicine technologists). A striking property of IVaraU is that it is highly physiologically potent per unit weight; for example, it effectively inhibits herpes virus at very low concentrations (approximately 1.times.10.sup.-9 g/mL, depending on the strain of herpes virus). Thus, fourthly, the administrable form must be in low molar concentrations but of high specific radioactivity. Fifthly, a "no carrier added" administrable form is, therefore, also required for best results. The latter would be extremely desirable for demonstration of anti-herpes therapy by the Auger method, as discussed below. Sixthly, considering [.sup.* I]IVaraU as a radiopharmaceutical, it is necessary that a pure administrable form be provided, i.e. free from accompanying by-products (for example, the isomer must be trans; the cis isomer is not valuable). These six criterion are, therefore, necessary for an acceptable administrable form.
Unfortunately, the literature on iodolabelling of other similar nucleosides indicates low radiochemical yields and significant decomposition. The literature on unlabelled arabinosyl uridines indicates that arabinosyl uridines are particularly unstable to heating; it is thought that the 2'hydroxy group of arabinose reacts readily with the pyrimidine base.
In view of the foregoing, efforts to produce a satisfactory administrable form of [.sup.* I]IVaraU have produced less than desirable results as judged by the above criteria, and it has become clear that a different approach from that of the prior art is required. In one such attempt, radiolabelling of IVaraU employed a trimethyl silyl vinyl precursor, dichloro iodobenzene [.sup.123 I]NaI, and an unlabelled NaI added carrier. While useful [.sup.123 ]IVaraU is produced, the radiochemical yield is far too low, i.e. approximately 10%, and the specific radioactivity is also low, since the NaI carrier was added. Further, the product is accompanied by many unidentified contaminants, i.e. by-products. Thus, the administrable form of the compound produced by that reaction is far less than desirable, according to the above criteria.
Accordingly, it would be of substantial advantage to the art to provide an administrable form of [.sup.* X]XVaraU which meets or substantially meets the above criteria of an acceptable administrable form and to provide a process for production thereof, as well as methods of use thereof.